Vascular conditions arise from a variety of causes, and in some cases, necessitate surgical or endovascular intervention. Trauma to the vascular system may also necessitate surgical intervention to treat the traumatized anatomy. The long-term implantation of vascular prostheses including vascular grafts, stent-grafts, and stents, and the application of treatment modalities, including balloon angioplasty are often undertaken to treat vascular conditions including vascular disease and vascular trauma.
Consequences of surgical intervention have been observed following implantation of vascular prostheses including vascular grafts, stent-grafts, stents, and other prostheses, particularly when an anastomosis is formed. The consequences of surgical intervention include, but are not limited to, inflammation, intimal hyperplasia, stenosis, and restenosis of the treated blood vessel near the formed anastomosis. Inflammation is a physiological response by a mammalian body to surgery, injury, irritation, or infection. An inflammatory response involves complex biological activities at chemical, cellular, tissue, and organ levels. Generally, an inflammatory response is a protective attempt to remove an injurious stimulus, as well as to initiate a healing process for the diseased or traumatized tissue. Intimal hyperplasia is a pathological condition in which an overabundant inflammatory response is initiated involving stimulation, migration, and proliferation of numerous cell types. Stenosis and restenosis are constrictions of the blood vessel lumen and may be caused by mechanisms including, but not limited to, compliance mismatch between the native vessel and the implanted vascular prosthesis, host tissue response to an implanted material, prior disease states, and infection. Stenosis and restenosis can progress to a point where additional surgical intervention is required to enlarge the blood vessel lumen diameter of the blood vessel or the implanted vascular prosthesis to establish a less restrictive conduit for blood flow.
Additional vascular conditions that may require surgical or endovascular intervention include, but are not limited to, vascular injury, vascular prophylactic intervention, vascular disease, phlebitis, intimal hyperplasia, vulnerable plaques, carotid plaques, coronary plaque, vascular plaque, aneurismal disease, vascular dissections, atherosclerotic plaques, atherosclerotic lesions, vascular infection, and vascular sepsis.
One approach to treatment of these vascular conditions involves local delivery of a suitable pharmaceutical or biologically active agent in a liquid vehicle within luminal spaces of a blood vessel at or near the site of the vascular condition. The liquid vehicle containing the pharmaceutical or biologically active agent is contacted with tissues of the luminal space at a vascular treatment site for a determined length of time (dwell time). However, this approach often requires extensive dwell times at the vascular treatment site to ensure adequate delivery and retention of the bioactive agent at the vascular treatment site to treat the vascular condition. Even with extensive dwell times, the delivery and retention of the bioactive agent at the vascular treatment site using this approach may be insufficient to treat the vascular condition.
Another therapeutic approach is the implantation of vascular prostheses having a pharmaceutical-containing coating to deliver a pharmaceutical to a lumen of a blood vessel or other vascular conduit. Examples of vascular prostheses having a pharmaceutical-containing coating include, but are not limited to, stents, stent grafts, grafts, and angioplasty balloons. Other examples of vascular prostheses having a pharmaceutical-containing coating are drug eluting stents and drug eluting stent grafts (DESs). DESs are used in the treatment of coronary artery disease and peripheral artery disease. A high degree of physician skill is often required to implant DESs without damaging or traumatizing surrounding vascular tissue. The treatment of a vascular condition by the implantation of DESs may require long term implantation of the vascular prosthesis. The long term implantation of the vascular prosthesis may also result in mechanical trauma to the vascular treatment site due to a nonlubricious nature of the pharmaceutical-containing coating. The long term implantation of the vascular prosthesis may also result in an unwanted tissue reaction at the vascular treatment site due to the components of the vascular prosthesis and/or the pharmaceutical-containing coating. Therefore it is desirable to have an improved method for treating vascular conditions that requires minimal physician skill to perform. It is desirable to have an improved method for treating vascular conditions that avoids long term implants.
Drug eluting balloons (DEBs) are additional examples of vascular prostheses having a pharmaceutical-containing coating. The literature discloses the use of DEBs for the treatment of coronary artery disease and peripheral artery disease (see e.g., U.S. Pat. No. 5,102,402, issued to Dror et al.). Dror et al. disclose placing a DEBs in a blood vessel lumen to treat the vessel wall, inflating the balloon, and contacting the balloon surface with the luminal vessel wall to deliver a pharmaceutical into the blood vessel wall. Another example of treatment using DEBs involves an angioplasty balloon having microneedles (see e.g., U.S. Pat. Nos. 5,171,217; 5,538,504; and 6,860,867). DEBs often require a high degree of physician skill to implement. The implantation of the DEBs may also result in mechanical trauma to the vascular treatment site due to the components of the DEBs and/or the pharmaceutical-containing coating. It is desirable to have improved methods for treating and preventing vascular conditions that are simple and easy to implement. It is also desirable to have methods for treating and preventing vascular conditions that avoid mechanical trauma to the vascular treatment site and are compatible with the delivery of a wide variety of pharmaceuticals.
In addition to delivering drugs to blood vessels from stents, stent-grafts, grafts, and other prostheses, intraluminal drug delivery methods include methods that chemically “pave” luminal surfaces of a blood vessel (see e.g., U.S. Pat. Nos. 5,213,580; 5,674,287; 5,749,922; and 5,800,538). These “paving” methods involve fixation, polymerization, and bonding of a drug delivery system to the lumen of a blood vessel. Degradation of such delivery systems ranges from days to weeks. The methods can be challenging as they involve chemical reactions with the blood vessel lumen. These chemical reactions may induce trauma to the vascular treatment site. It is desirable to have improved methods for treating and preventing vascular conditions which avoid “paving” of the luminal surfaces of the blood vessel.
Methods of delivering drugs to perivascular locations are described. U.S. Pat. No. 6,726,923, issued to Iyer, and U.S. Pat. No. 5,527,532, issued to Edelman, disclose perivascular drug eluting wraps and matrices applied to adventitial surfaces of a blood vessel to treat vascular inflammation.
U.S. Pat. No. 5,893,839, issued to Johnson, discloses a method of treating restenosis involving the delivery of a biologically active substance percutaneously.
U.S. Pat. No. 6,730,313, issued to Helmus et al., discloses a method for treating intimal hyperplasia involving contacting an exterior surface of a blood vessel with a “flowable” drug delivery vehicle.
These methods usually require complex procedural techniques, often implemented through invasive surgical techniques. In addition, these methods may require long term implantation of a vascular prosthesis, drug eluting wraps, matrices, and flowable drug delivery vehicles. Long term implantation of the vascular prosthesis, drug eluting wraps, matrices, and flowable drug delivery vehicles may also result in an unwanted tissue reaction at the vascular treatment site due to the nature of their components. It is desirable to have improved methods for treating and preventing vascular conditions that allow delivery of a wide variety of pharmaceuticals and biologics to diseased or traumatized vascular tissue without the need for long term implants, that are easily implemented, and that are applied through surgical and endovascular techniques.
Li et al. (U.S. Patent Application Publication 2002/0019369) disclose an injectable cyclodextrin polymer-based composition made from cyclodextrin, polyethylene glycol, and a pharmacologically effective amount of at least one drug. Li et al. further disclose their composition can be used subcutaneously, intramuscularly, intradermally, or intracranially. However, Li et al. do not teach their composition can be injected into the vasculature or into flowing blood.
As is disclosed to the literature, compositions made of cyclodextrin and polyethylene glycol form inclusion complexes. The inclusion complexes have the form of hydrogels, turbid solutions, and precipitates (Li, J Biomed Mater Res, 65A, 196, 2003; Harada, Macromolecules, 26, 5698, 1993; Harada, Macromolecules, 23, 2821, 1990).
Indeed, as indicated by the literature, injection of particles in the form of hydrogel materials, turbid solutions, and precipitates into the vasculature or into flowing blood can have adverse consequences, including decreased drug effectiveness, phlebitis, embolism, and blockage of capillaries (Nemec, Am J Heath Syst Pharm, 65, 1648, 2008; Wong, Adv Drug Del Rev, 60, 939, 2008; Minton, Nutrition, 14, 251, 1998; Tian, Polym Int, 55, 405, 2006). Instructions for use of an injectable pharmaceutical solution contraindicate injection into the vasculature or flowing blood if the injectable pharmaceutical solution is turbid or contains precipitates.
There remains a need for improved vascular-based therapies to treat a variety of vascular conditions. The improved therapies would be easily implemented and would obviate mechanically or chemically induced trauma to the vascular treatment site. The improved therapies would allow for administration of thixotropic, turbid, bioactive agent-containing gel materials to vascular tissue at a vascular treatment site. The gel material would readily release one or more bioactive agents contained by the gel material to vascular tissue in need of treatment or repair. The gel material would dissolve in the flowing blood without occluding vascular structures located distally (i.e., downstream) to the administration site. The therapies could be applied prophylactically, interventionally, surgically, or endovascularly.